Glucagon-like peptide-2 (GLP-2) is a 33 amino acid peptide expressed in a tissue-specific manner from the pleiotropic glucagon gene. GLP-2 shows remarkable homology in terms of amino acid sequence to glucagon and Glucagon-Like Peptide-1 (GLP-1). Further, different mammalian forms of GLP-2 are highly conserved. For example, the human GLP-2 and degu (a south American rodent) GLP-2 differ from rat GLP-2 by one and three amino acids respectively. When given exogenously, GLP-2 can produce a marked increase in the proliferation of small intestinal epithelium of test mice, apparently with no undesirable side effects (Drucker et al., 1996, PNAS:USA 93:7911-7916). Subsequently it was shown that peptide analogs of native GLP-2 with certain modifications to the peptide sequence possess enhanced trophic activity at the small intestine (see co-pending application U.S. Ser. No. 08/669,791, filed Jun. 28, 1996, incorporated herein by reference). It has further been demonstrated that GLP-2 can proliferate the tissue of the large intestine (co-pending applications U.S. Ser. No. 08/763,177, filed Dec. 10, 1996, and U.S. Ser. No. 08/850,664, filed on May 2, 1997, and Litvak et al., 1997, Gastroenterology, vol. 112 (4 Suppl.), page A1455, all of which are incorporated herein by reference). Moreover, GLP-2 has also been shown to increase D-glucose maximal transport rate across the intestinal basolateral membrane (Cheeseman and Tseng, 1996, American Journal of Physiology 271:G477-G482).
A number of peptide hormones, structurally unrelated to GLP-2, have been demonstrated to have varying degrees of trophic activity. For example, Insulin-Like Growth Factor-2 (IGF-2) has been shown to promote mitosis of the crypt cells of the small intestine in vivo (U.S. Pat. No. 5,482,926). Insulin-Like Growth Factor-1 (IGF-1), which shares 64% sequence identity with IGF-2, and peptide analogs thereof have also been shown to increase the growth of gut tissue in vivo (WO 91/12018). Growth Hormone (GH) has been shown to have a number of physiological effects, including increasing proliferation of the intestinal mucosa (see, for example, Willmore, U.S. Pat. No. 5,288,703), thereby enhancing the absorptive capacity of the gut. However, none of the above peptide hormones possess the efficacy or specificity of GLP-2 in promoting proliferation of the tissue of the lower gastrointestinal tract.